CCL17 (thymus and activation regulated chemokine, TARC), is a chemokine ligand for CCR4. CCL17 is constitutively expressed in thymus, and upon activation is produced by a number of cellular sources, including PBMCs, monocytes, macrophages, dendritic, endothelial, and bronchial cells (Imai et al., J Biol Chem, 271:21514-21, 1996; Sallusto et al., Eur J Immunol, 29:1617-25, 1999; Campbell et al., Nature, 400:776-80, 1999; Sekiya et al., J Immunol, 165:2205-13, 2000).
CCL17 induces chemotaxis of CCR4 expressing cells (mainly Th2 and cutaneous T lymphocytes), and is thus implicated in the maintenance of Th2 immune responses (Imai et al., Int Immunol, 11:81-8, 1999), as well as in the suppression of classically-activated macrophages (Katakura et al., J Immunol, 172:1407-13, 2004). Neutralization of CCL17 has been shown to reduce Th2 cytokines, airway eosinophilia and hyperresponsiveness in allergen-induced asthma (Kawasaki et al., J Immunol, 166:2055-62, 2001), and protect from pulmonary fibrosis (Belperio et al., J Immunol, 173:4692-8, 2004). CCL17 expression levels correlate with the disease phenotype in chronic allergic pathologies, including asthma (Leung et al., Eur Respir J, 21:616-20, 2003), atopic dermatitis (Jahnz-Rozyk et al., Allergy 60:685-8, 2005) and cutaneous lupus erythematosus (Wenzel et al., J Invest Dermatol, 124:1241-8, 2005). Thus, modulators of CCL17 signaling, such as neutralizing anti-CCL17 antibodies, may have a therapeutic benefit for inflammatory, allergic, and fibrotic conditions.
Predictive pharmacokinetic, safety and efficacy studies will be required before any CCL17 modulator for human use can be brought to the market place. Such studies will involve both in vitro and in vivo testing in animal models of CCL17-associated pathologies. Lack of cross-reactivity of the modulators with human CCL17 orthologs can pose a challenge in these studies. Thus, use of, antibody-based CCL17 modulators may require evaluation of cross-reactivity of the antibodies across species, generation of surrogate antibodies against a CCL17 polypeptide expressed by a particular model animal, as well as significant in vitro characterization of such surrogate antibodies. Evaluation of cross-reactivity, surrogate generation and in vitro characterization will require the use of CCL17 polynucleotides and polypeptides from a suitable animal model.
Thus, a need exists for the identification of polynucleotides encoding CCL17 and CCL17 polypeptides being expressed in an animal model identified as suitable for the predictive pharmacokinetic, safety and efficacy studies of CCL17 modulators. A need also exists for related methods such as methods of expressing such polypeptides and testing the cross-reactivity of CCL17 modulators.